DE-A-199 12 461 discloses a device for flow rate limitation at low differential pressures, particularly for limiting the volumetric inhalation flow during inhalation of therapeutic aerosols. The device consists of a housing including an aspiration orifice, an inhalation orifice and a flow passage disposed therebetween. The flow passage has a flat elongate cross-section with flexible large-area walls. The cross-section of the flow passage is adapted to be reduced as a function of the differential pressure prevailing between the inhalation orifice and the aspiration orifice as well as of the flexibility of the material of the walls to a size appropriate for a predetermined volumetric maximum inhalation flow.
The administration of drugs in aerosol form by inhalation into the lungs is influenced essentially by four factors: (i) the particle size and the particle properties of the aerosol; (ii) the patient's tidal volume; (iii) the patient's respiratory flow; and (iv) the patient's morphometry and respiratory system. So far, the known systems have produced aerosols with suitable particle size ranges, however, they have only insufficiently or not at all considered the parameters “tidal volume” and “respiratory flow” (respiratory velocity). The aerosol inhalation is therefore uncontrolled so that the amount of aerosol particles provided to the lungs is insufficient or the lung areas to be treated (such as the alveolic area) are not at all provided with aerosol particles.
EP-A-0 965 355 discloses a device for a controlled inhalational administration of controlled dosage drugs into the lungs. This controlled inhalator comprises a closed recipient that is adapted to be charged with a predeterminable aerosol volume and from which the aerosol can be extracted via of a control means for the inhalation flow rate. In this known inhalator, the control means is either a controllable valve or a critical nozzle. The tidal flow can be limited by the use of a controllable valve or a critical nozzle.
EP-B-0 050 654 discloses an inhalation apparatus for administering pulmonary medication. This apparatus comprises an inflatable envelope from which an aerosol may be inhaled by means of a mouthpiece. Before inhalation, this aerosol is introduced into the inflatable envelope from a cartridge via a nebulizer. For limitation of the air flow rate through the mouthpiece during the inhalation, the mouthpiece is provided with a restriction. This restriction limits the tidal flow during the inhalation.
The two aforementioned inhalation devices are characterised in that the flow rate is limited so that during the inspiration phase the tidal volume is increased merely slowly and the increase in the tidal flow is decreased continuously. Thus, in a diagram showing the tidal flow over time, the graph is continuously flattened. On account of this flow limitation, the tidal flow increases in different manners to a maximum flow value as a function of the patient's sucking capacity. This results in an almost constant flow rate so that in the known inhalators the flow rate limitation may lead to a more constant aerosol deposition in the lungs.
EP-A-1 036 569 discloses a method and a device for providing a predetermined constant medicament dose for an inhalational administration at a low inhalation flow rate. This device comprises a closed container whose volume is reducible, a mouthpiece which is connected to the container and may be joined with a powder aerosol inhalator for providing a powder aerosol, a closed inner housing which surrounds the container, whose volume is reducible and from which the mouthpiece extends in a sealed manner and means for controlling the air flowing into or out of the area between the container and the housing. The housing may be brought from a state of reduced volume to a predetermined expanded state for filling the container with the predetermined aerosol volume.
Moreover, EP-A-1 038 544 discloses a device for flow rate limitation at low differential pressures, particularly for limiting the volumetric inhalation flow during inhalation of therapeutic aerosols. This device consists of a housing with at least one aspiration orifice, at least one inhalation orifice and a flow space disposed therebetween and including at least one flexible wall having a cross-section which can be reduced as a function of the differential pressure prevailing between said inhalation orifice and said aspiration orifice and of the flexibility of the wall material up to a predetermined dimension for a definable maximum volumetric inhalation flow.
Moreover, U.S. Pat. No. 5,655,520 discloses a flexible valve for administering constant flow rates of medicine.
U.S. Pat. No. 5,842,467 discloses a metered dose inhaler.
EP-A-1 136 921 discloses an inhalation device comprising a self-expandable container for a predetermined aerosol volume, means for disbursing an aerosol from an aerosol dispenser into the container and control means for controlling the inhalation flow. The control means keeps the inhalation flow essentially constant during the entire aerosol inhalation and comprises four flow channels radially extending between a central admission opening and discharge openings that are radially spaced apart from the admission opening. The four radially extending flow channels are formed by four radially arranged rectangular webs extending from an essentially rigid wall to an essentially flexible wall. One web thereof is longer than the others.
The present invention is based on the object of providing an improved control means and an improved valve that is in particular applicable in an inhalation device and supplies the tidal volume necessary for the aerosol inhalation irrespective of the patient's characteristics while being suitable for variable applications. This object is achieved by a valve or an inhalation device having the features of the claims.
The inhalation device of the present invention keeps the inhalation flow essentially constant during the entire aerosol inhalation and comprises a controllable valve for limiting the flow rate through the control means. The valve is preferably a variable flow limiter which, for example, allows for a continuous or gradual flow control.
The controllable valve according to the invention preferably comprises a housing, a set piston, a flexible wall (such as a membrane or an elastomer disk), an optional pressure plate, a closure element and an adjusting screw. The housing is preferably essentially tubular and comprises a plurality of, e.g. four, radially arranged webs, one of which is longer than the others. These webs extend from the tubular wall of the housing radially inwards in an axial view, the webs are arranged in a central portion of the housing so that on one side of the webs the housing is adapted to adjustably receive the set piston and on the opposite side of the webs it is adapted to receive the membrane or elastomer disk, the pressure plate and the closure element.
Moreover, the inhalation device according to the present invention is preferably designed such that the elastomer disk is forced against the webs of the housing by means of the pressure plate and the closure element so that a space is formed between the membrane and the set piston. To this end, the set piston comprises a plurality of, e.g. four, recesses that are radially arranged at the housing in correspondence with the webs, preferably at an end face facing the elastomer disk, one recess being longer than the others. A plurality of, e.g. two, admission openings are provided between two adjoining webs. These admission openings are for example on a common circumferential line and are spaced apart from each other by 45°. In an inner area of the set piston facing away from the recesses, the admission openings run into a common central flow channel. To this end, the set piston preferably consists of two parts. The first part comprises the recesses with the admission openings and the second part, which is preferably permanently connected, e.g. glued, to the first part, comprises the central flow channel to which the admission openings are connected.
The set piston is preferably sealingly received by the housing. Moreover, the adjusting screw may preferably be axially fixed to the set piston so that the set piston is axially adjustable with respect to the housing via the adjusting screw. To this end, the adjusting screw is preferably provided with an external thread that is engageable with a corresponding internal thread provided in the housing. By adjusting the adjusting screw, the piston may thus be axially shifted so that the webs provided at the housing may be inserted into the recesses provided at the set piston at will.
According to a further embodiment, the controllable valve according to the present invention is gradually adjustable. To this end, a sliding block guide is provided between the set piston and the housing. Moreover, the components of the controllable valve are essentially identical to those of the first embodiment.
Preferably, the controllable valve is connected to an inhalation limiter. The inhalation flow rate limitation for example consists of an inhalation bag, a bucket wheel or a ventilation channel that is closed after a predetermined period of time. The administered volume may be inferred from the predetermined flow rate and the measured inhalation time. As soon as this is achieved, the admission opening is closed. This means that the flow rate is indirectly measured by measuring the inhalation time. Both a mechanical as well as an electronic measurement of the volume is conceivable.
An inhalation device comprising the controllable valve according to the present invention keeps the inhalation flow rate essentially constant during the entire aerosol inhalation. Thus, the inhalation flow rate is increased to a maximum value directly at the beginning of the inspiration phase, which is necessary for a sufficient aerosol administration, and is held at this maximum value as long as a minimum pressure is generated by the patient during the inhalation. Preferably, this minimum pressure is not exceeding 10 mbar and is preferably in a range between 5 and 10 mbar. Thus, a flow rate limitation is already achieved at low differential pressures.
The inhalation device preferably combines a container, particularly self-expanding container, for a predetermined aerosol volume, means for disbursing an aerosol from an aerosol dispenser into the container and control means for controlling the inhalation flow rate, wherein the control means comprises a controllable valve according to the invention so as to keep the inhalation flow rate essentially constant during the entire inhalation.
The flow channel preferably runs into the inside of the housing which surrounds the aerosol container. Before the aerosol inhalation, the aerosol is led into the inside of the container from, e.g., a cartridge, preferably via a nozzle, such as a nebulizer or a controlled aerosol dosing supply. The container expands until in its fully expanded state an aerosol volume that is determined by the container volume is generated inside the container. Alternatively, it is also possible to arrange the aerosol volume directly at the nebulizer or at the aerosol dosing supply.
When the patient sucks the aerosol out of the container via a preferably provided mouthpiece, the container shrinks on account of the suction. The low pressure generated inside the housing is compensated via the flow channel. The generated low pressure arches the flexible wall towards the inside of the flow channel as a function of the extent of the low pressure so that the cross-section of the flow channel is reduced. This reduction in cross-section results in a limitation of the air flow through the flow channel into the housing inside for pressure compensation reasons, which in turn limits the aerosol flow out of the container. Already at pressures of 10 mbar, the control means automatically controls the flow rate within the flow channel and automatically controls the tidal flow.
The low pressure generated during the aerosol inhalation directly reduces the cross-section of the flow channel on account of the flexible wall, i.e. directly to a threshold value. Thus, the tidal flow threshold value is already reached at the beginning of the inhalation and essentially kept during the entire inhalation at pressures of 80 to 100 mbar, which are usually generated by the suction of the lungs.
The means for disbursing an aerosol from an aerosol dispenser into the container prevents a drug, such as corticoids, in the form of an aerosol from being dispensed directly from the aerosol dispenser into the oral cavity and from being inhaled. Rather, the patient is required to introduce the aerosol from the aerosol dispenser into the container and subsequently inhale the predetermined aerosol volume defined by the container by means of the inhalation according to the present invention. Preferably, the aerosol dispenser, such as a cartridge, is connected with a nozzle via a collar and secured to the inhalation device. The aerosol is introduced into the inside of the container via the nozzle.
The inhalation device according to the invention has a plurality of advantages. The inhalation device according to the invention allows for a uniform and precise drug dosage irrespective of the patient's coordination. On account of the different container volumes, the desired deposition location in the lungs and the desired aerosol amount is pre-selectable. If the housing is at least in part transparent, the inhaled volume may be controlled visually since the patient is capable of observing the container folding up. The inhalation device according to the invention allows for a simple handling and at the same time a high effectiveness. By dispensing the active ingredient into the container before the inhalation, the aerosol disbursement from the dispenser is restricted to the necessary amount so as to prevent excessive consumption. An accurate and efficient dosage results in low treatment costs, e.g., for a treatment with corticoids. A further advantage of the present invention consists in that the use of a propellant, e.g., for the administration of corticoids, is not absolutely necessary.
The term “suitable drugs” as used here includes active ingredients, drugs, compounds, compositions or mixtures of substances that have a pharmacological, often advantageous effect. Food, dietary supplements, nutrients, drugs, vaccines, vitamins and other useful active ingredients are thus included. The terms used here furthermore include all physiologically or pharmacologically active ingredients having a local or systemic effect in a patient. The active ingredient that may by administered in aerosol form includes antibodies, antiviral substances, anti-epileptics, analgesics, anti-inflammatory substances and bronchodilators and can be an organic or inorganic composition which, without any restrictions, includes drugs having an effect on the peripheral nervous system, adrenergic receptors, cholinergic receptors, skeletal muscles, cardiovascular system, unstriated muscles, circulatory system, neuronal junctions, endocrine or hormonic system, immune system, reproductive system, skeletal system, food intake and excretory system, histamine cascade or central nervous system. Suitable active ingredients may, e.g., be polysaccharides, steroids, hypnotics and sedatives, stimulants, tranquilizers, anticonvulsives and muscular relaxants, anti-parkinson drugs, analgesics, anti-inflammatory agents, antimicrobial substances, antimalarial drugs, hormones including contraceptives, symphaticomimetics, polypeptides and proteins having physiologic effects, diuretics, substances regulating the lipometabolism, anti-androgenic substances, antiparasitics, neoplastics and antineoplastics, antidiabetics, foodstuff and dietary supplements, growth-stimulating substances, fats, bowel regulators, electrolytes, vaccines and diagnostic agents. Combinations of active ingredients (compound preparations) are also possible. Moreover, systemic drugs (such as insulin) may also be administered.
The present invention is particularly suited for (but not restricted to) the application of different active ingredients by inhalation, such as:
Insulin, calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, cyclosporin, granulocyte colony stimulating factor (GCSF), alpha-1 proteinase inhibitor, elcatonin, granulocyte makrophage colony stimulating factor (GMCSF), growth hormones, human growth hormones (HGH), growth hormone releasing hormones (GHRH), heparin, low-molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), somatostatin, somatostatin analogues including octreotide, vasopressin analogues, follicle stimulating hormone (FSH), insulin-like growth factor, insulinotropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (MCSF), nerve growth factor, parathyroid hormone (PTH), thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, antibodies against respiratory syncytical viruses, cystic fibrosis transmembrane regulator gene (CFTR), desoxyribonuclease (DNase), bactericides, permeability-increasing protein (BPI), anti-CMV antibodies, interleukin-1 receptor, retinol, retinyl ester, tocopheroles and their esters, tocotrienols and their esters, carotinoides, in particular beta carotene and other natural and synthetic anti-oxidants, retinol acids, pentamidines, albuterol sulfate, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, ipratropium bromide flunisolides, fluticasones, cromolyn sodium, ergotamine tartrate and their analogues, agonists and antagonists of the aforementioned substances. Active ingredients may further include nucleic acids in the form of pure nucleic acid molecules, viral vectors, associated viral particles, nucleic acids associated with or contained in lipids or a lipid-containing material, plasmid DNA or RNA or other nucleic acid constructs suitable for cell transfection or transformation, particularly in cells of the alveolic parts of the lungs. The active ingredient may have different forms, such as soluble or insoluble loaded or unloaded molecules, components of molecular complexes or pharmacologically accepted adjuvants. The active ingredient may consist of natural molecules or their recombinantly produced molecules, or the molecules may be analogues of the natural or recombinantly produced active ingredients in which one or more amino acids have been added or deleted. Moreover, the active ingredient may comprise weakened virus vaccines or dead viruses for vaccination. In case of the active ingredient insulin, naturally extracted human insulin, recombinant human insulin, bovine and porcine extracted insulin, recombinant porcine and bovine insulin and mixtures of the aforementioned insulin types. The insulin may be pure, i.e. substantially purified, but can also comprise commercially available extracts. The term “insulin” also comprises insulin analogues in which one or more of the amino acids of the natural or recombinant insulin have been added or deleted. In particular, the inhalation device according of the present invention is suitable for the administration of vitamin A or vitamin A ester and retinoic acid or retinoic acid ester, also in combination with natural and synthetic antioxidants.